Dibenzodiazocyclotetradecadiene compounds

ABSTRACT

3,4,10,11-Dibenzo-1,8-diazacyclotetradeca-3,1-dienes and pharmaceutically acceptable acid addition salts useful as hypoglycemic agents, obtained by cyclization of the N-formyl derivatives of phenylpropylamine or substituted phenylpropylamines to form dihydrobenzazepin, which is dimerized to the corresponding dibenzodiazacyclotetradecatetraene, which is then reduced to the corresponding diazacyclotetradecadiene.

United States Patent Goldman et al.

[54] DIBENZODIAZOCYCLOTETRADECA DIENE COMPOUNDS [72] Inventors: Irving M. Goldman, Niantic; Jerry K. Larson, New London, both of Conn.

[73] Assignee: Pfizer Inc., New York, NY.

[22] Filed: June 2, 1969 [21] Appl. No.: 829,714

[52] U.S. Cl. ..260/239 DD, 260/239 BB, 260/301, 260/340.3, 260/340.5, 260/465 E, 260/556 A, 260/556 AR, 260/56l R, 260/562 R, 260/570.8 R,

424/244 [51] Int. Cl. ..C07d 53/00 [58] Field of Search ..260/239 DD, 340.3, 340.5

[5 6] References Cited UNITED STATES PATENTS 3,497,499 2/1970 Houlihan etal. ..260/239 51 July 11, 1972 OTHER PUBLICATIONS Stetter, Chemical Abstracts, Vol. 49, cols. 8315- 83 16 1955) Primary Examiner-Alton D. Rollins Attorney-Connolly and Hutz [5 7] ABSTRACT 4 Claims, No Drawings BACKGROUND OF THE INVENTION This invention relates to new and useful benzazepine compounds which are effective in reducing blood sugar levels. More particularly, it is concerned with certain novel tetrahydrobenzazepine dimers and their pharmaceutically-acceptable acid addition salts which are useful as oral hypoglycemic agents.

In the past, various attempts have been made by investigators in the field of medicinal chemistry to obtain new and useful oral hypoglycemic agents. For the most part, these efforts have involved the synthesis and testing of various novel sulfonylureas and related compounds. However, in the search for still newer and better oral hypoglycemic agents, relatively little is known about the activity of non-sulfonylureas. This is particular true in the case of the subject benzazepine derivatives where the chemistry has not yet been extensively explored.

SUMMARY OFTHE INVENTION In general, this invention is concerned with novel dihydrobenzazepine dimer intermediates and the reduction to corresponding tetrahydrobenzazepine dimers which are surprisingly useful as hypoglycemic agents. The novel compounds of this invention have the following formulas:

and

DETAILED DESCRIPTION OF THE INVENTION Instrumental in the elucidation of those novel Schiff base dimerizations were studies that included the analyses of infrared, nuclear magnetic resonance and mass-spectral data. A

representative (or general) reaction scheme is shown in Chart I. In the corresponding reaction, with the cyclization of the N- acetyl derivative of phenylpropylamine, only the monomer is obtained (Chart II). The azomethine-methyl group provides steric hindrance to the dimerization process.

REACTIDN SCHEME Ghart I CH2CH2CH2NH *CIIzCHzCIIzNH O HO II. II.

' N-OHzR R R CHzR-U R 3 ifi R R ll (EH3 1H: .11..

In accordance with the process employed for preparing the novel compounds of this invention, 3-phenylpropylamine or substituted 3-phenylpropylamine, is first converted to the N- formyl derivative by, for example, treatment with a formic acid-toluene mixture at reflux with azeotropic removal of water. The crude monomeric cyclization product, obtained by Bischler-Napieralski reaction of the N-formyl derivative with, for example, polyphosphoric acid/phosphorus pentoxide, is spontaneously transformed on standing to the crystalline benzazepine dimer. The dimer intermediate is then reduced to the saturated amine under mild conditions by the use of lithium aluminum hydride or a metal borohydride such as sodium, potassium or lithium borohydride in accordance with any number of conventional organic procedures previously described in the literature. Still another pertinent reaction procedure in this connection involves the use of hydrogenation catalysts, such as platinum or palladium on carbon, for example.

The cyclization of the N-formyl-3-phenylpropylamine is carried out by heating polyphosphoric acid to about 95-l05 C. under nitrogen in a three-neck flask fitted with a slow mechanical stirrer. Phosphorus pentoxide is added all at once with stirring and the temperature is raised to about l40-l60 C. The N-formyl-3-phenylpropylamine is added with stirring over a 5-10 minute period, and the temperature is raised to about l55-l65 C. After stirring for -20 hours, the mixture is cooled to about 80-90 C., and slowly poured into a large volume of ice water. The resulting mixture is extracted with several portions of a water-immiscible organic solvent such as benzene or toluene to remove unreacted starting material. The aqueous layer is made weakly alkaline (pH 7-9) with ammonia or KOl-l pellets with stirring and cooling. The resulting mixture is extracted with several portions of an organic solvent such as chloroform, carbon tetrachloride, methylene chloride, ethylene dichloride, ether or benzene, backwashed with water, and the solvent dried over anhydrous magnesium or sodium sulfate. Removal of the solvent affords a viscous oil which crystallizes on standing for about 4-72 hours. The crude solid, a mixture of the dihydrobenzazepine monomer and dimer, is carefully triturated with cold acetone to remove soluble acidic impurities. Repeated recrystallizations, from large volumes of hot acetone followed by rapid addition of water, for example, or from acetone/ethanol, affords the pure white dihydrobenzazepine dimer.

For the cyclization of the N-formyl-3-phenylpropylamine, a number of variations in the procedure may be employed. The condensing reagent may be polyphosphoric acid and/or phosphorus pentoxide or a polyphosphoric ester prepared from phosphorus pentoxide and diethyl ether in chloroform solution and used in situ. The condensing reaction may be run by heating the reactants in the presence of reaction-inert solvents such as benzene, toluene, xylene, and the like. In practice, it is most convenient to heat the reactants in a solvent of the aforementioned type for approximately 1-24 hours.

The dimeric di-Schiff bases of this invention are prepared by leaving the crude or pure monomeric Schiff bases (Bischler-Napieralski cyclization products) at ambient temperatures in the absence of solvent for up to several days. Crystallization of the dimeric di-Schiff base is spontaneous, but may be facilitated by addition of appropriate seed crystals. While the monomer to dimer conversion is most easily accomplished at room temperature, temperatures as low as 0 C. and as high as 60 C. may also be used. While the conversion of monomer to dimer is self-catalyzed, the addition of proton or Lewis acids in catalytic amounts may facilitate the dimerization. Isolation of the dimer, once formed, is best accomplished by trituration with an inert solvent such as acetone or alcohol to remove impurities. Purification of the dimer may be achieved by recrystallization from organic solvents, while avoiding acidic impurities such as hydrogen chloride in chloroform. Acetone, ethanol and benzene are examples of suitable solvents.

The reaction step of the process that involves the reduction of the benzazepine dimer to the corresponding tetrahydro derivative may be effected with lithium aluminum hydride in a reaction-inert organic solvent such as ether or tetrahydrofuran, or with one of the aforementioned borohydride complexes in methanol. 1n the preferred process, an excess of sodium borohydride is added over a 5-15 minute period with stirring to a methanolic solution of the dimer. After stirring for 1-2 hours, the methanol is removed in vacuo. The residue is taken up in a mixture of water and chloroform, and extracted several times with chloroform. The solvent extracts are dried over anhydrous magnesium sulfate. The removal of the solvent affords the crystalline diamine reduction products which may be recrystallized from suitable solvent mixtures or converted to appropriate acid addition salts.

Alkylation of the dimeric diamines may be carried out by methods known to those skilled in the art. Where R CH;,, the methyl group can be introduced by the use of the formaldehyde-formic acid procedure. Where R lower alkyl or substituted alkyl, the N,N-dialkylated tetrahydrobenzazepine dimers may be prepared conveniently by first preparing the diacyl derivatives via treatment of the tetrahydrobenzazepine dimers with the appropriate acid anhydride or acid chloride in pyridine, chloroform with an acid acceptor such as pyridine or triethylamine, or benzene with an acid acceptor. The diacylated derivatives are then reduced with lithium aluminum hydride. The reduction is best carried out by treatment with lithium aluminum hydride in refluxing diethyl ether or tetrahydrofuran for approximately 1-24 hours. Workup of the reduction reaction with water followed by extraction with an organic solvent such as chloroform, ethyl acetate or benzene affords the pure, N,N-dialkylated products. Exceptions to this general reaction scheme are tetrahydrobenzazepine dimers substituted with NHCOCH; or CN groups, or other groups that are sensitive to the action of acylating agents or lithium aluminum hydride.

Inasmuch as the benzazepine compounds of this invention are basic compounds, they are capable of forming a wide variety of salts with various mineral and organic acids. Although such salts must be pharmaceutically-acceptable when the final products are intended for oral consumption, it is possible to first isolate the desired benzazepine compounds from the reaction mixture as a phannaceutically unacceptable salt and then to subsequently convert the latter, as indicated previously, to the free base compound by treatment with an alkaline reagent, followed by the final conversion to the pharmaceutically-acceptable salt in the manner, hereinafter indicated. For instance, the acid addition salts of the benzazepine compounds of this invention may be prepared by treating the basic compound with a substantially equivalent amount of the chosen acid. The salt-formation step can be carried out in an aqueous solution or in a suitable organic solvent such as methanol or ethanol. The solid salt may separate out directly, or upon careful evaporation of the solvent, the solid salt is obtained.

The acids which are used to prepare the pharmaceuticallyacceptable acid addition salts of the aforementioned benzazepine bases of this invention are those which form nontoxic acid addition salts containing pharmaceutically acceptable anions, such as the hydrochloride, hydrobromide, hydriodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, gluconate, saccharate, methanesulfonate, ethanesulfonate, benzenesulfonate and ptoluenesulfonate salts.

As previously indicated, the benzazepine compounds of this invention may be readily adapted to therapeutic use as oral hypoglycemic agents. They have shown good hypoglycemic activity in the normal fasted rat at dose levels ranging from about mg/kg to about 70 mg/kg.

For purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and dicalcium phosphate may be employed along with various disintegrants such as starch and preferably potato or tapioca starch, alginic acid and certain complex silicates together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules. When aqueous suspensions and/or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.

This invention is still further illustrated by the following examples, which are not to be construed in any way or manner as imposing limitations upon the scope thereof. On the contrary, it is to be clearly understood that resort may be had to various other embodiments, modifications and equivalents thereof which readily suggest themselves to those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

EXAMPLE 1 Intermediate-3 ,4, l 0,1 l-dibenzo- 1 ,S-diazacyclotetradeca- 1,3,8, 1 O-tetraene Polyphosphoric acid (950 g.) is heated to 100 C. under nitrogen in a 2-liter, three-neck flask fitted with a slow mechanical stirrer. Phosphorus pentoxide (95 g.) is added all at once with stirring and the temperature raised to 150 C. N; formyl;3:phenylpropylamine (54 g.) is added with stirring over about 5 minutes and the temperature is raised to 160 C. After stirring for 16 hours the brown mixture is cooled to 80-90 C. and slowly poured with stirring into 5 liters of ice water. The resulting mixture is extracted with five 500 ml. por; tions of benzene to remove unreacted starting material. The aqueous layer is made weakly alkaline (pH 7-8) by slow addition of KOH pellets with stirring and cooling. The resulting mixture is extracted with six 500 m1. portions of chloroform and the extracts are combined, backwashed with several small portions of water and dried over anhydrous magnesium sulfate. Removal of chloroform in vacuo affords 29 g. of crude product as a tan oil which solidifies on standing for 24 hours. Trituration of the solid mass with several portions of cold acetone affords 19 g. of tannish crystalline material, m.p. 132; 135C. Recrystallization from 1.9 liters of hot acetone, with rapid addition of about 500 ml. of water to cause rapid precipitation of the product, affords 13.8 g. of white, crystalline material, m.p. 162-164 C. Two more recrystallizations from acetone/water affords 10.3 g. (17 percent) of the pure white compound m.p. 172-173 C. A sample was sublimed at 145 C. (0.01 mm.) for analysis, m.p. l72.5-173 C.

Anal. Mass spectrum, m/e (70 eV) 290. Calcd. for C H N is recrystallized from methylene chloride/ethanol to give 9.42 g. of the tetrahydro dimer, m.p. l59-160 C. The mother liquors afford a second crop, 0.65 g. m.p. l57-159 C. Recrystallization from methylene chloride/ethanol affords 9.24 g. (60 percent) of the pure reduced compound, m.p. l64164.5 C. An intraperitoneal injection of this tetrahydro dimer at a dose range of 30-40 mgJkg. lowers the blood sugar of anaesthetized rats about 15-20 percent.

Anal. Mass spectrum, m/e (70 eV) 294. Calcd. for C H N C, 81.55; H, 8.85; N, 9.52. Found: C, 81 .80; H, 9.09; N, 9.48.

EXAMPLE 11 lntermediate;3,4,l0,l 1-(3,3',4,4;tetramethoxydibenzo);1,8- diazacyclotetradecafl ,3 ,8, l O-tetraene In a l liter three-neck flask is placed 70 g. of polyphosphor: ic acid and 250 ml. of benzene. The mixture is heated to about 50 C. to facilitate stirring, and 35 g. of phosphorus pentoxide is added. To the stirred mixture is added 5.0 g. of N formyl- 3,4-dimethoxyphenylpropylamine, and the reaction mixture is heated at reflux for 1.2 hours. At the end of this time, the benzene layer is discarded. Ice is then added to the residue with stirring, and 4.1 g. of starting material is recovered by extraction with three portions of chloroform. The acidic aque: ous phase is basicified with concentrated ammonia to pH 9 and extracted with chloroform. The chloroform extracts, after drying, yield an oil which solidifies upon standing for 16 hours. After trituration with cold acetone, the material is recrystallized from acetone/methanol followed by recrystallization from acetone to give the pure dimer m.p. 246.5-247.5 C.

Anal. Mass spectrum, m/e (70 eV) 410. Calcd. for C H O N C, 70.22; H, 7.36; N, 6.82. Found: C, 70.22; H, 7.36; N, 6.61. Reduction to 3,4,10,1 l;( 3 ,3 ',4,4;tetramethoxydibenzo);1,8- diazacyclotetradeca;3,IO-diene To a mixture of the above compound (704 mg.) in 40 ml. of methanol is added sodium borohydride (1.4 g.) with stirring over 10 minutes. After stirring for 1 hour, the methanol is removed in vacuo and the residue is worked up to yield 595 mg. of the crude tetrahydro benzazepine dimer. Recrystallization from benzene/hexane affords the pure compound as white crystals, m.p. 181.5-182 C.

Anal. Mass spectrum, m/e (70 eV) 414. Calcd for C H O,

C, 69.53;H, 8.27; N, 6.76.

Found: C, 69.47; H, 8.14; N, 6.82.

An intraperitoneal injection of this tetrahydro dimer at a dose range of 10:20 mg./kg. lowers the blood sugar of anaesthetized rats about 5%; at 30-35 mg./kg. the blood sugar is lowered about 10-15%; at 60-65 mg./kg. the drop in blood sugar is about 5l0%.

EXAMPLE I11 1ntermediate;3,4,10,1 1-(2,2'4,4-tetramethoxydibenzo )-l ,8- diazacyclotetradeca; 1 ,3,8, l 0 tetraene To a stirred mixture of phosphorus pentoxide 14 g.) in 200 ml. of benzene is added N;formyl;3,5;dimethoxyphenyl: propylamine (4.0 g. The mixture is heated under reflux for 3 hours. After removal of the benzene in vacuo, addition of ice, and extraction with 4 small portions of chloroform to remove neutral material, the acidic aqueous layer is basicified with concentrated ammonia and exhaustively extracted with chloroform. Standard workup of the chloroform extracts af; fords 2.48 g. of crude product as a brown oil which solidifies on standing overnight. Trituration with acetone/ethanol af: fords the first crop, 346 mg. of the crystalline dimer m.p. 196; 199C. Evaporation of solvent from the triturates and short; path distillation at 0.1 mm. affords 1.15 g. of a yellowish oil which solidifies on standing overnight. Trituration with ethanol affords a second crop, 1.02 g. of dimer, m.p. l75-185 C., which on recrystallization from ethanol/methylene chloride affords 0.91 g. of the dimer as a white crystalline solid, m.p. l94-l 96 C. Recrystallization of the combined solids from acetone affords the pure dimer, m.p. 205206 C.

Anal. Mass spectrum, m/e (70 eV) 410. Calc'd. for C H O C, 70.22; H, 7.36; N, 6.82.

Found: C, 70.07; H, 7.43; N, 6.69. Reduction to 3 ,4, 1 0,1 l-(2,2,4,4';tetramethoxydibenzo)- l ,8- diazacyclotetradeca-3,l;diene To a mixture of 486 mg. of the above in 25 ml. of methanol is added with stirring 958 mg. of sodium borohydride over 4 minutes. The solution is left at room temperature for 2.5 hours. Workup in the usual way affords 311 mg. of the pure tetrahydro dimer from methylene chloride/hexane, m.p. 187-188 C.

Anal. Mass spectrum, m/e (70 eV) 414. Calcd. for C,,H,,,N

C, 69.53; H, 8.27; N, 6.76.

Found: C, 69.53; H, 8.31; N, 6.70.

An intraperitoneal injection in anaesthetized rats at a dose range of about 60-70 mg./kg. lower the blood sugar about 10-15 percent.

EXAMPLE IV The N,N'-dimethyl derivative of the tetrahydro dimer of Ex; ample I is prepared by adding 5.0 g. of 97 percent formic acid with cooling to 2.94 g. (0.01 mol.) of the dimer. To this clear solution is added 4.5 g. of 37 percent formaldehyde solution. The mixture is heated on a steam bath for four hours with evolution of CO. The solution is cooled, acidified with 5 ml. of 4N HCl and evaporated in vacuo to an oil. Water is added and the solution is basicified to pH 9 with 10% NaOH solution, and extracted with 3 portions of methylene chloride. The com; bined extracts are dried over magnesium sulfate and evaporated to an oil which is passed through a column of Alu; mina (Woelm, Activity 11) in chloroform to give, after recrystallization from methylene chloride/ethanol, 2.66 g. of the pure dimethyl derivative, m.p. 7l71.5 C.

Anal. Mass spectrum, m/e (70 eV) 322. Calcd. for C H N An intraperintoneal injection in anaesthetized rats at a range of 15-20 mg./kg. lowers the blood sugar about 5-10 percent.

EXAMPLE V The N,N'-dimethyl derivative of the tetrahydrobenzazepine dimer of Example I1 is prepared by the method of Example IV, with comparable hypoglycemic activity.

EXAMPLE VI The N,N'-dimethyl derivative of the tetrahydrobenzazepine dimer of Example 111 is prepared by the method of Example IV, with comparable hypoglycemic activity.

EXAMPLE VII EXAMPLE VIII The N-formyl derivatives of the following compounds are cyclized and then reduced to the corresponding tetrahydrobenzazepine dimers by the method of Example I, with comparable hypoglycemic acitivity.

EXAMPLE IX The N,N-dimethyl derivatives of the compounds of Example VIII are prepared by the method of Example IV with comparable hypoglycemic activity.

EXAMPLE X The N,N'-diethyl derivative of 3,4,l0,1 l-dibenzo-l ,8-diazacyclotetradeca-3,lO-diene is prepared by stirring 294 mg. (0.001 mol.) of the tetrahydrobenzazepine dimer in acetic anhydride (5 ml.) and pyridine (1 ml.) for about 16 hours at room temperature. The excess acetic anhydride and pyridine are removed in vacuo and the resulting crude product is recrystallized from ethanol/hexane to yield the diacetyl derivative, m.p. 2 l 0-212 C. Alternately, acetyl chloride may be used in place of acetic anhydride.

To a mixture of the diacetyl derivative (378 mg. 0.001 mol.)

40 in 10 ml. of dry tetrahydrofuran is added an excess of lithium aluminum hydride (38 mg. 0.001 mol.). The mixture is heated under reflux for about 16 hours. The excess reagent is decomposed by the careful addition of wet ether, and the product is exhaustively extracted into tetrahydrofuran. Removal of the solvent after drying over anhydrous magnesium sulfate and recrystallization from methylene chloride/hexane affords a near quantitive yield of the pure N,N-diethyl derivative.

EXAMPLE XI The N,N'-dialkyl derivatives of the tetrahydrobenzazepine dimers of Example 11, Example 111 and Example VIII, except for tetrahydrobenzazepine dimers substituted with NHCOCH or CN groups, or other groups that are sensitive to the action of acylating agents or lithium aluminum hydride, are prepared by the general procedure of Example X employing appropriate acid anhydrides or acyl halides, followed by reduction with lithium aluminum anhydride, to provide the following dialkyl groups:

ethyl p py butyl isobutyl benzyl phenylethyl EXAMPLE XII The acid-addition salts of the tetrahydrobenzazepine dimers of Examples I, III, IV, V, VI, VII], IX, X and XI are prepared by the method of Example V11, with hypoglycemic activity comparable to the free bases.

EXAMPLE XIII A suspension is prepared with the following composition:

70% aqueous sorbitol Glycerine, U.S.P.

Gum acacia solution) Polyvinylpyrrolidone Distilled water 74l.29 grams [8535 grams l00.0 ml.

0.5 grams sufficient to make 1 liter Sufficient 3,4,10,1 1-(3,3',4,4-tetramethoxydibenzo)-l,8- diazacyclotetradeca-3,IO-diene is added to achieve a concentration of 23 mg. of effective ingredient per milliliter. To this suspension, various sweeteners and flavorants may be added to improve the palatability of the suspension.

EXAMPLE XIV A tablet base is prepared by blending the following ingredients in the proportions by weight indicated:

Maize starch 20.0 Dibasic calcium phosphate 74.0 Alginic acid l6.0

Into this tablet base is blended sufficient 3,4,l0,l1-(3,3',4,4'- tetramethoxydibenzo l ,8-diazacyclotetradeca-3 l O-diene to provide tablets containing 20, 100 and 250 mg. of active ingredient per tablet. The composition is compressed into tablets, each weighing 360 mg, by conventional means.

EXAMPLE XV A solution of 3,4,10,ll-(3,3,4,4-tetramethoxydibenzo)- l,8-diazacyclotetradeca-3, l O-diene hydrochloride is prepared with the following composition:

Effective ingredient 2.5 grams Polyethylene glycol-200 400 ml. Water, distilled ml.

The resultant solution has a concentration of effective ingredient of 5 mg./ml., and is suitable for all forms of parenteral administration.

What is claimed is: 

2. 3,4,10,11-(3,3'',4,4''-tetramethoxydibenzo)-1,8-diazacyclotetradeca-3,10 -diene.
 3. 3,4,10,11-(2,2'',4,4''-tetramethoxydibenzo)1,8-diazacyclotetradeca 3,10-diene.
 4. N,N'' -dimethyl-3,4,10,11-dibenzo-1,8-diazacyclotetradeca-3, 10-diene. 